Recent findings by Schuckit point to initial sensitivity/acute tolerance as an important predictor of the subsequent development of alcoholism in young males. The marked similarity of biochemical and physiological reactions to ethanol as well as the similarity of the genome between mouse, rat and man, provides the Rosetta stone for discovering which genes are responsible for increased risk for alcoholism in man. This proposal is designed to discover which genes are responsible for initial sensitivity to ethanol in the rat (High and Low alcohol Sensitive lines) and compare the findings with other rat models of alcohol preference (Preference and NonPreference rats and High Alcohol Dependent and Low Alcohol Dependent rats, developed by Dr. T-K. Li) as well as with a mouse model of initial sensitivity (Short and Long Sleep mice from the Institute for Behavioral Genetics) and the acute tolerance model in mice under development by Dr. Erwin (the High Alcohol Function Tolerance and Low Alcohol Functional Tolerance mice). The likelihood that a gene is involved in alcohol reactions in man if it is found in both mice and rats is greatly increased. On the other hand, there are substantial differences between rats and mice in ethanol related reactions but at this point we do not know which more closely resembles the human condition. This has been the goal of studies of genetics of ethanol actions in rodents for the last 25 years and the tools for doing so are now at hand.